tbuckley/cabot-search huggingface dataset:
VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia
Authors: Steven Sher, Ethan Whipp, Janek Walker, Pu Zhang, Larry Beaver, Katie Williams, Shelley Orwick, Janani Ravikrishnan, Brandi Walker, Elizabeth Perry, Charles Gregory, Matthew Purcell, Alexander Pan, Pearlly Yan, Lapo Alinari, Amy J. Johnson, Melanie M. Frigault, Joy M. Greer, Ahmed Hamdy, Raquel Izumi, Xiaokui Mo, Deepa Sampath, Jennifer Woyach, James Blachly, John C. Byrd, Rosa Lapalombella
Journal: Leukemia (2022)

Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.
CD16+ fibroblasts foster a trastuzumab-refractory microenvironment that is reversed by VAV2 inhibition
Authors: Xinwei Liu, Yiwen Lu, Jingying Huang, Yue Xing, Huiqi Dai, Liling Zhu, Shunrong Li, Jingwei Feng, Boxuan Zhou, Jiaqian Li, Qidong Xia, Jiang Li, Min Huang, Yuanting Gu, Shicheng Su
Journal: Cancer Cell (2022)
Food odor perception promotes systemic lipid utilization
Authors: Hiroshi Tsuneki, Masanori Sugiyama, Toshihiro Ito, Kiyofumi Sato, Hiroki Matsuda, Kengo Onishi, Koharu Yubune, Yukina Matsuoka, Sanaka Nagai, Towa Yamagishi, Takahiro Maeda, Kosuke Honda, Akira Okekawa, Shiro Watanabe, Keisuke Yaku, Daisuke Okuzaki, Ryota Otsubo, Masanori Nomoto, Kaoru Inokuchi, Takashi Nakagawa, Tsutomu Wada, Teruhito Yasui, Toshiyasu Sasaoka
Journal: Nature Metabolism (2022)
Transmembrane water-efflux rate measured by magnetic resonance imaging as a biomarker of the expression of aquaporin-4 in gliomas
Authors: Yinhang Jia, Shangchen Xu, Guangxu Han, Bao Wang, Zejun Wang, Chuanjin Lan, Peng Zhao, Meng Gao, Yi Zhang, Wenhong Jiang, Biying Qiu, Rui Liu, Yi-Cheng Hsu, Yi Sun, Chong Liu, Yingchao Liu, Ruiliang Bai
Journal: Nature Biomedical Engineering (2022)
Attitudes About Extremely Preterm Birth Among Obstetric and Neonatal Health Care Professionals in England
Authors: Katie Gallagher, Chloe Shaw, Maryam Parisaei, Neil Marlow, Narendra Aladangady
Journal: JAMA Network Open (2022)

Variation in attitudes between health care professionals involved in the counseling of parents facing extremely preterm birth (<24 wk gestational age) may lead to parental confusion and professional misalignment.To explore the attitudes of health care professionals involved in the counseling of parents facing preterm birth on the treatment of extremely preterm infants.This qualitative study used Q methods to explore the attitudes of neonatal nurses, neonatologists, midwives, and obstetricians involved in the care of extremely preterm infants in 4 UK National Health Service perinatal centers between February 10, 2020, and April 30, 2021. Each participating center had a tertiary level neonatal unit and maternity center. Individuals volunteered participation through choosing to complete the study following a presentation by researchers at each center. A link to the online Q study was emailed to all potential participants by local principal investigators. Participants ranked 53 statements about the treatment of extremely preterm infants in an online quasi-normal distribution grid from strongly agree (6) to strongly disagree (-6).Distinguishing factors per professional group (representing different attitudes) identified through by-person factor analysis of Q sort-data were the primary outcome. Areas of shared agreement (consensus) between professional groups were also explored. Q sorts achieving a factor loading of greater than 0.46 (P < .01) on a given factor were included.In total, 155 health care professionals volunteered participation (128 [82.6%] women; mean [SD] age, 41.6 [10.2] years, mean [SD] experience, 14.1 [9.6] years). Four distinguishing factors were identified between neonatal nurses, 3 for midwives, 5 for neonatologists, and 4 for obstetricians. Analysis of factors within and between professional groups highlighted significant variation in attitudes of professionals toward parental engagement in decision-making, the perceived importance of potential disability in decision-making, and the use of medical technology. Areas of consensus highlighted that most professionals disagreed with statements suggesting disability equates to reduced quality of life. The statement suggesting the parents' decision was considered the most important when considering neonatal resuscitation was placed in the neutral (middistribution) position by all professionals.The findings of this qualitative study suggest that parental counseling at extremely low gestations is a complex scenario further complicated by the differences in attitudes within and between professional disciplines toward treatment approaches. The development of multidisciplinary training encompassing all professional groups may facilitate a more consistent and individualized approach toward parental engagement in decision-making.
Gut microbiome, cognitive function and brain structure: a multi-omics integration analysis
Authors: Xinxiu Liang, Yuanqing Fu, Wen-ting Cao, Zhihong Wang, Ke Zhang, Zengliang Jiang, Xiaofang Jia, Chun-ying Liu, Hong-rou Lin, Haili Zhong, Zelei Miao, Wanglong Gou, Menglei Shuai, Yujing Huang, Shengdi Chen, Bing Zhang, Yu-ming Chen, Ju-Sheng Zheng
Journal: Translational Neurodegeneration (2022)

Microbiome-gut-brain axis may be involved in the progression of age-related cognitive impairment and relevant brain structure changes, but evidence from large human cohorts is lacking. This study was aimed to investigate the associations of gut microbiome with cognitive impairment and brain structure based on multi-omics from three independent populations.
Transfer Learning assisted PodNet for Stimulation Frequency Detection in Steady state visually evoked potential-based BCI Spellers
Authors: Elham Rostami, Farnaz Ghassemi, Zahra Tabanfar
Journal: Brain-Computer Interfaces (2022)

Convolutional Neural Networks (DCNNs) can be a useful tool for detecting the stimulus frequency of the SSVEP signal. The transfer learning approach is used to improve the performance of the PodNet in the presence of a low amount of training data. In this research, two publicly available, 35-subject Benchmark and 70-subject BETA databases are used. In the rendered method, information is transferred from a model trained on the large BETA database to a secondary model which has been designed to identify target stimulus frequency in single-participant of the Benchmark database. The results show that the accuracy (95.00 %) and ITR (143.13 bpm) of the proposed approach in single-participant are significantly higher than the CCA (p < 0.05) and the PodNet (p < 0.00001). This study illustrates that using the transfer learning approach can improve the performance of the PodNet in the case of limited training data.
Association Between Primary Care Use Prior to Cancer Diagnosis and Subsequent Cancer Mortality in the Veterans Affairs Health System
Authors: Edmund M. Qiao, Kripa Guram, Nikhil V. Kotha, Rohith S. Voora, Alexander S. Qian, Grace S. Ahn, Sandhya Kalavacherla, Ramona Pindus, Matthew P. Banegas, Tyler F. Stewart, Michelle L. Johnson, James D. Murphy, Brent S. Rose
Journal: JAMA Network Open (2022)

Primary care physicians (PCPs) are significant contributors of early cancer detection, yet few studies have investigated whether consistent primary care translates to improved downstream outcomes.To evaluate the association of prediagnostic primary care use with metastatic disease at diagnosis and cancer-specific mortality (CSM).This cohort study used databases with primary care and referral linkage from multiple Veterans' Affairs centers from 2004 to 2017 and had a 68-month median follow-up. Analysis was completed between July 2021 and September 2022. Participants included veterans older than 39 years who had been diagnosed with 1 of 12 cancers. Inclusion criteria included known clinical staging, survival follow-up, cause of death, and receiving care at the Veterans Affairs health system (VA).Prediagnostic PCP use, measured in the 5 years prior to diagnosis. PCP visits were binned into none (0 visits), some (1-4 visits), and annual (5 visits).Metastatic disease at diagnosis, cancer-specific mortality (CSM) for entire cohort and stratified by tumor subtype.Among 245 425 patients representing 12 tumor subtypes, mean age was 65.8 (9.3) years, and the cohort skewed male (97.6%), and White (76.1%), with higher levels of comorbidity (58.6% with Charlson Comorbidity Index scores ≥2). Compared with no prior visit, some PCP use was associated with 26% decreased odds of metastatic disease at diagnosis (odds ratio [OR], 0.74; 95% CI, 0.71-0.76; P < .001) and 12% reduced risk of CSM (subdistribution hazard ratio [SHR], 0.88; 95% CI, 0.86-0.89; P < .001). Annual PCP use was associated with 39% decreased odds of metastatic disease (OR, 0.61; 95% CI, 0.59-0.63; P < .001) and 21% reduced risk of CSM (SHR, 0.79; 95% CI, 0.77-0.81; P < .001). Among tumor subtypes, prostate cancer had the largest effect size for prior PCP use on metastatic disease at diagnosis (OR for annual use, 0.32; 95% CI, 0.30-0.35; P < .001) and CSM (SHRfor annual use, 0.51; 95% CI, 0.48-0.55; P < .001).In this cohort study, increased primary care use before cancer diagnosis was associated with significant decreases in metastatic disease at diagnosis and cancer-related death, with potentially the greatest difference from annual use. PCPs play a vital role in cancer prevention, and additional resources should be allocated to assist these physicians.
IMMU-03. ANALYSIS OF EXPRESSION SIGNATURES OF MATCHED PRIMARY GASTROINTESTINAL CANCER AND BRAIN METASTASES USING NANOSTRING NCOUNTER TECHNOLOGY
Authors: Azad Cheko, Georgiana Burnside, Hannes Vogel, Melanie Hayden Gephart, Claudia Petritsch
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Brain metastases from the gastrointestinal tract are a rare event (less than 10% of all brain lesions), but their impact on prognosis is remarkable. Their incidence is increasing due to earlier diagnosis and prolonged survival because of more effective treatment modalities. Because of the lack of evidence-based recommendations, no optimal treatment strategy has been defined. Hope might come from the discovery of new prognostic and predictive factors and their biological inhibitors. The aim of this study was to create a repository of matched primary cancer and brain metastases samples for clinicopathologic and molecular correlations of gastrointestinal tumors and to analyze changes in expression signatures between both samples. The main goal was to study the metastatic process and characterize the immune response by characterizing features such as invasiveness, vascular co-option, proliferation, stemness and cell-type heterogeneity between the matched tissues. METHODS We searched for patients at Stanford hospital with matched brain metastases from gastrointestinal tumors from 2008 to 2020 using the STARR database (The STAnford Research Repository, or STARR, is Stanford Medicine's approved resource for working with clinical data for research purposes.). Matched specimens mean that both brain metastases and gastrointestinal tumors were studied at Stanford University. FFPE blocks from these matched patients were sectioned and sections analyzed for gene expression analysis using nanoString nCounter technology and the immune-oncology panel. RESULTS Expression data from 32 matched patients with primary tumor and brain metastases will be discussed at the meeting. CONCLUSION We believe that analysis of changes in expression signatures between the matched primary gastrointestinal cancer and brain metastases will provide novel insights into the role for tumor factors, such as invasiveness, proliferation and stemness, and the tumor microenvironment in progression.
NIMG-104. PRE-OPERATIVE LANGUAGE FUNCTIONAL MRI (FMRI) FOR LOCALIZATION OF THE RIGHT VENTRAL PREMOTOR CORTEX (VPMC) IN COMPARISON WITH DIRECT CORTICAL STIMULATION
Authors: Arpita Sahu, Antariksh Vijan, Prakash Shetty, Parthiban Velayutham, Aliasgar Moiyadi
Journal: Neuro-Oncology (2022)

Abstract PURPOSE To assess the concordance of pre-operative language functional MRI (fMRI) for localization of the right ventral premotor cortex (vPMC) in comparison with Direct Cortical Stimulation. METHODS AND MATERIALS Prospective analysis was performed for 11 (n=11) patients with right-sided tumors who underwent language mapping by fMRI, followed by awake neurosurgery and intra-operative mapping by Direct Cortical Stimulation (DCS). Multi-paradigm language fMRI was performed using a standard 3-paradigm language protocol, with additional tongue movement paradigm on a Phillips Ingenia, 1.5T Scanner. The vPMC was identified as BOLD signal activation seen in at least two paradigms anterior to and discrete from the motor orofacial cortex. Pre-operative fMRI findings were validated intra-operatively using DCS with the intra-operative responses of anarthria (speech arrest) and dysarthria recorded separately. RESULTS We obtained moderate concordance (sensitivity) of 72.2% (n=8) for anarthria (speech arrest). The vPMC was the site of speech arrest in 75% cases (n=6), followed by the oro-facial motor cortex in the remainder (n=2, 25%). Higher frequency of vPMC activation was seen with Tongue Movement and Number Counting paradigms, while that of Broca’s area with Verb Generation. Tumour size &amp;gt;5cm, presence of peritumoral edema and intra-tumoral haemorrhage were some of the features associated with fMRI-DCS discordance. CONCLUSIONS vPMC detection by fMRI shows good concordance (sensitivity) with anarthria responses on Direct Cortical Stimulation. Thus, fMRI serves as a useful non-invasive tool in pre-operative planning for maximal safe resection of brain tumors.
NIMG-76. MORPHOLOGIC CHANGES TO THE HIPPOCAMPI FOLLOWING SURGICAL RESECTION AND ADJUVANT CHEMORADIATION IN PATIENTS WITH HIGH GRADE TEMPORAL GLIOMAS
Authors: Luis Fernandez, Daniel Oyon, William Gibson, Mandana Behbahani, Osaama Khan, Shelly Sharma
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The hippocampus is known to remodel in pathologic conditions including epilepsy and Alzheimer’s disease. Literature investigating the effect of high-grade gliomas (HGGs) on the hippocampus following resection and adjuvant chemoradiation are limited; no study has evaluated these effects in tumors exclusively in the temporal lobe. METHODS A retrospective chart review was conducted on 30 patients with temporal HGGs who underwent craniotomy for resection with adjuvant RT and TMZ. Brainlab Elements was used to manually contour bilateral hippocampal gray matter volumes in the subgranular zone using T1-precontrast MRI sequences (1.5 mm thickness or less) pre-resection and at time of most recent follow up. These volumes were compared using a student’s t-test with significance set at p&amp;lt; 0.05. RESULTS Average follow up time was 23.5 months from initial resection. Average pre-treatment hippocampal volumes in this temporal glioma cohort compared to healthy controls from prior studies were 2.93 vs 2.83 cm3 (right, p=0.31) and 2.78 vs 2.76 cm3 (left, p=0.39) respectively. Pre vs post resection right hippocampal volumes in patients with right sided lesions were 2.59 vs 1.75 cm3 (p=.002). Left hippocampal volumes in patients with left sided tumors were 2.99 vs 1.64 cm3 pre and post resection respectively(p=0.0009). No significant differences in hippocampal volumes contralateral to the tumor side were found following treatment (p=0.31 and 0.07 for right and left hippocampi respectively). CONCLUSIONS Temporal gliomas are in close anatomic proximity to the hippocampi also may invade and/or disrupt local circuits which output to the hippocampi. Resection and chemoradiation are correlated with decreased hippocampal volumes ipsilateral to the primary locus of disease. Further characterization of hippocampal subregions, particularly the dentate gyrus, in addition to results of neuropsychiatric testing pre and post treatment are necessary to better elucidate the clinical implications of these morphologic changes and the putative functional networks which underlie them.
CSIG-34. LIN28B-LET-7-PBK PATHWAY IS AN IMPORTANT REGULATOR OF GROUP 3 MEDULLOBLASTOMA PROLIFERATION
Authors: Shubin Shahab, Jessica Sun, Haritha Kunhiraman, Matthew Schneiderjan, Kyle Juraschka, Sachin Kumar, Michael Taylor, Tobey MacDonald, Anna Kenney
Journal: Neuro-Oncology (2022)

Abstract Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and many do not survive beyond 5 years. Several drivers for Group 3 MB have been identified but none have resulted in targeted therapy to date. LIN28B is a stem cell factor upregulated in Group 3 MB and is associated with worse survival. Here we investigate the role of the LIN28B pathway in Group 3 MB development. Pharmacologic inhibition of the LIN28B pathway is feasible and may provide a unique opportunity to target this tumor. Using LIN28B knockdown and overexpression in Group 3 MB cells we test LIN28B’s effect on proliferation, self-renewal and metastasis. We investigate the effect of LIN28B knockdown on survival as well as proliferation and apoptosis markers using orthotopic xenografts in vivo. We also investigate the role of let-7 and its downstream target PBK on Group 3 MB proliferation. Finally, we use a LIN28 inhibitor 1632 and a PBK inhibitor HITOPK032 to treat Group 3 MB cell lines and then assess their impact on proliferation and apoptosis. We find that down-regulation of LIN28B or PBK using shRNA results in significant reduction in cell proliferation. In contrast overexpression of LIN28B increases Group 3 cell proliferation and tumor sphere formation. LIN28B knockdown also significantly (p&amp;lt; 0.01) increases survival in mice with orthotopic Group 3 tumors. The LIN28 inhibitor 1632 also leads to significant reduction in MB growth through decreased cell cycle entry and increased apoptosis. In addition, HITOPK032 also demonstrates significant reduction in Group 3 MB cell proliferation at low micromolar concentration. We also demonstrate that HITOPK032 in combination with CDK 4/6 inhibition can additively inhibit proliferation of Group 3 MB cells. Our study establishes a critical role for the LIN28B-let-7-PBK pathway in Group3 MB and provides encouraging preliminary preclinical results for drugs that target this pathway.
TMET-30. ENHANCED RADIOSENSITIZATION OF GLIOMAS BY METABOLIC TARGETING OF SALVAGE PATHWAY OF NAD SYNTHESIS THROUGH NAMPT INHIBITION
Authors: Pratibha Sharma, Jihong Xu, Longfei Huo, Zhenlin Ju, Ziyi Li, Kechen Ban, Yosef Landesman, Deepa Sampath, Vinay Puduvalli
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Pathway-specific targeted agents have failed to improve outcome in patients with high grade gliomas. Tumor recurrence is driven by glioma heterogeneity and emergence of therapy-resistant subpopulations. We have previously reported that metabolic targeting of NAMPT, the rate limiting enzyme in the NAD salvage synthesis pathway, circumvents glioma heterogeneity and induces cytotoxicity by mitochondrial membrane depolarization and generation of reactive oxygen species. Based on these data, we examined the potential for NAMPT inhibition to synergize with ionizing radiation to enhance glioma cytotoxicity in vitro and in vivo. METHODS Using a panel of genetically heterogeneous patient-derived glioma stem-like cells (GSC), we examined the effects of NAD targeting using KPT9274, a potent NAMPT inhibitor, in combination with ionizing radiation on cell proliferation and clonogenicity using Cell Titre Glo assay, colony formation assays and secondary sphere formation. Changes in DNA damage-related proteins were visualized by immunofluorescence assay and confocal microscopy. Effects on gene expression and protein levels were assessed using western blot, reverse phase protein array (RPPA) and RNA Seq. RESULTS NAMPT inhibition reduced cell proliferation rate, self-renewal and clonogenic capacity in vitro. Combining KPT-9274 with ionizing radiation caused synergistic inhibition of secondary sphere and colony formation of GSC. RPPA and RNASeq results showed downregulation of several DNA repair proteins which was further confirmed using immunofluorescence staining indicating a crucial role for these proteins in glioma resistance to therapies. Results of ongoing in vivo studies to assess the PK/PD, drug toxicity and survival benefits of this combination therapy in orthotopic GSC intracranial glioma mouse model will be reported. CONCLUSIONS Our results suggest that metabolic targeting through NAMPT inhibition sensitizes glioma cells to radiotherapy. Ongoing studies delineating the mechanistic basis of these effects and their impact in vivo as a potential rationale for clinical assessment will be reported.